"glycolysis I And Ii"

Front 1

What are the glucose transporters?

Back 1

GLUT-1
--In all mammalian cells
--Easily saturated (Km=1), so not good for high glucose concentrations.

GLUT-2
--In liver and pancreatic B cells
--Not easily saturated (Km=15-20), so great for liver and pancreas, where glucose is high

GLUT-3
--In all mammalian cells

GLUT-4
--In muscle/fat cells

GLUT-5
--In small intestine.

Front 2

What is role of glycolysis in liver?

Back 2

--Energy source
--Lipid precursors (glucose-->fat)
--Glycogen source--First step in glycolysis is also step in glycogen synthesis.

Front 3

What is role of glycolysis in muscle?

Back 3

--Energy source
--Glycogen source--First step in glycolysis is also step in glycogen synthesis.

Front 4

What is role of glycolysis in adipose?

Back 4

--Energy source.
--lipid precursors (glucose-->fat)

Front 5

What is role of glycolysis in brain?

Back 5

--Practically only source of energy
--Lipid precursors (glucose-->fat)

Front 6

What is role of glycolysis in RBCs?

Back 6

--ONLY energy source--can't use anything else!

Front 7

What is role of glycolysis in other tissues?

Back 7

--Energy
--Lipid precursors (glucose-->fat)

Front 8

What are the steps in glycolytic pathway?

Back 8

"PREPPING" the sugar--

glucose--(hexokinase)-->G-6-P--(phosphoglucose isomerase)-->F-6-P--(PFK-1)-->F-1,6-bisP

"SPLITTING" the sugar

F-1,6-bisP--(fructose bisphosphate aldolase)-->SPLIT into glyceraldehyde-3-phosphate (G-3-P) AND DHAP (not useful--must be converted to G-3-P by triose phosphate isomerase

"ENERGY YIELDING" step

G-3-P--(G-3-P dehydrogenase)-->1,3-bisphosphoglycerate--(phosphoglycerate kinase)-->3 phosphoglycerate--(phosphoglycerate mutase)-->2-phosphoglycerate-->phosphoenolpyruvate--(pyruvate kinase)-->Pyruvate

if anaerobic...
Pyruvate--LDH-->LACTATE

Front 9

What is regulation of glycolysis using glucose transporters?

Back 9

--Adipose/muscle possess GLUT-4 transporter-->movement to membrane stimulated by insulin-->will increase GLUT-4 transporters-->more glucose comes in-->more glycolysis.

Front 10

What is regulation of glycolysis using Glucose phosphorylation?

Back 10

Hexokinase
--phosphorylates glucose in muscle-->forms G-6-P
--Inhibited by G-6-P--feedback inhibition!
--If PFK-1 or PK are inhibited, G-6-P increases-->inhibits hexokinase-->inhibits glycolysis. This is what occurs in fasting.

Glucokinase (GK)
--phosphorylates glucose in liver-->forms G-6-P
--Active only when glucose is high--good, because, when glucose is low, will NOT be active--save glucose for RBC's and brain.

Front 11

What are some features of glucokinase (GK)?

Back 11

--GK has lower glucose affinity than hexokinase--insulin release/liver glycolysis increases in fed state and decrease in fasting state--hexokinase is saturated easily, so less difference b/w states.
--GK is activated by glucose--inactive when glucose is low--keeps glycolysis off.
--GK is induced by insulin--when insulin is low, GK is inactive (good, because only active during fed state)

...Overall, shows you that the FIRST step in liver glycolysis will be ACTIVE in FED state, but OFF in FASTING state.

Front 12

How is glycolysis regulated by PFK-1?

Back 12

--PFK-1 is the rate-limiting step in glycolysis.
--INHIBITED by: ATP, citrate, protons.
--Fed state-->prevents excess fat production by glycolysis.
--Fasting state-->don't need glycolysis--using B-oxidation--saving glucose for brain, RBC's.

--ACTIVATED by:
AMP, F-2,6-bisP
AMP--shows cell needs more energy/glycolysis

Front 13

Describe glycolysis inhibition by glucagon thru F-2,6-bisP

Back 13

--PFK-2 is a dual kinase/phosphatase that converts F-6-P-->F-2,6-BisP
KINASE--F-6-P-->F-2,6-BisP
PHOSPHATASE--F-2,6-BisP-->F-6-P
--F-2,6-BisP activates PFK-1-->activates glycolysis.
-->to INHIBIT glycolysis-->want to turn off KINASE (less F-2,6-BisP) and turn on PHOSPHATASE (F-2,6-bisP-->F-6-P)
--SO, glucagon binds receptor->activates adenylate cyclase-> activates cAMP->activates protein kinase A->phosphorylates PFK-2->activates PHOSPHATASE and inhibits KINASE-->decreases F-2,6-bisP levels-->PFK-1 is not activated->less glycolysis.

Front 14

What happens to PFK-2 when insulin increases again?

Back 14

-->a phosphatase is activated-->PFK-2 de-phosphorylated-->KINASE activated again
-->also can lower cAMP levels-->decrease PKA-->lead to dephosphorylation of enzyme-->increases KINASE activity and decreases PHOSPHATASE activity-->increases F-2,6-bisP-->increase PFK-1 activity-->increases glycolysis!

Front 15

How is PFK-2 activation/inhibition handled in the muscle?

Back 15

Remember--in muscle, epinephrine increases glycolysis (need energy when you work out)
--So, instead of INHIBITING PFK-2, Epi activates it-->stimulating F-2,6-bisP production.
-->Epi uses same receptor mechanism as glucagon, so would expect the same reaction..
-->Why? Because PFK-2 in muscle is an ISOFORM--phosphorylation by PKA actually DECREASES PHOSPHATASE activity and INCREASES KINASE activity.

Front 16

How is glycolysis regulated by pyruvate kinase (PK)?

Back 16

--INHIBITED by ATP and alanine.
--shows that energy needs are being met in the cell.
ATP--plenty of energy--don't need glycolysis
Alanine--shows gluconeogenesis is happening--don't need glycolysis.
--FASTING (don't want glycolysis)-->cAMP-->PKA-->PHOSPHORYLATES PK-->inactivates it
--FED (want glycolysis)-->insulin-->phosphatase-->DEPHOSPHORYLATES PK-->activates it.

Front 17

What is importance of 2, 3 bisphosphoglycerate (2,3-BPG)?

Back 17

RBC's require 2,3-BPG to bind O2 to hemoglobin.
--RBC's have enzymes that allow it to be generated from glycolytic intermediates.

1/2 glucose-->1, 3 BPG--(2,3-BPG mutase)-->2,3-BPG--(2,3 BPG phosphatase)-->re-enters glycolysis as 3-phosphoglycerate

--"sneaks" in at the very end of glycolysis
*bypassing ATP producing reactions.

Front 18

How does fructose get into glycolysis?

Back 18

Liver makes fructokinase

Fructose--(fructokinase)-->F-1-P--(aldolase B)-->glyceraldehyde--(triose kinase)-->G-3-P-->lactate OR DHAP

--BYPASSES the regulated PFK-1 step (F-6-P-->F-1,6-BisP)

Front 19

How does galactose get into glycolysis?

Back 19

Galactose--(galactokinase)-->Galactose-1-Phosphate

Galactose-1-P + UDP-glucose--(galactose-1-phosphaste uridyl transferase)-->UDP-galactose (w/uridine) + GLUCOSE-1-P--(UDP-galactose-4-epimerase)-->UDP-glucose

GLUCOSE-1-P converted to G-6-P by phosphoglucomutase-->can enter glycolysis

Front 20

How does glycerol get into glycolysis?

Back 20

Glycerol--(glycerol kinase)-->Glycerol phosphate--(glycerol phosphate dehydrogenase)-->DHAP

Front 21

What is pyruvate kinase deficiency?

Back 21

--Type of hexoase metabolism disorder.
--leads to anemia.

Front 22

What is Warburg phenomenon?

Back 22

--type of hexose metabolism disorder
--when tumor forms, it has no blood supply
--must survive by glycolysis and TF's

Front 23

What is galactosemia?

Back 23

--No galactokinase
--accumulation of galactose--(aldose reductase)-->galacticol-->osmotically active-->cataracts!

Front 24

What is uridyl transferase deficiency?

Back 24

--no uridyl transferase
--accumulate galactose, galactose-1-P
--get cataracts, but gal-1-P is toxic-->failure to thrive

Front 25

What is fructose intolerance?

Back 25

--Deficiency of fructokinase--not too bad--extra-hepatic tissues can metabolize fructose using hexokinase.
--Deficiency of aldolase B--more serious, because blocks metabolism of F-1-P-->accumulation of F-1-P ties up phosphate-->decreases ATP-->degradation of accumulated AMP can worsen gout.
-->also, F-1-P is toxic to liver.

Front 26

What is fructose toxicity?

Back 26

--ingestion of large amounts of fructose.
--Bypass PFK-1 step (stated earler)
--Excess fructose-->converted to fat
-->although F-1-P can be metabolized, it still accumulates-->leads to fructose intolerence.

Front 27

How are carbohydrates digested/absorbed?

Back 27

Breaking down POLYsaccharides (starch, glycogen) and DIsaccharides (lactose, sucrose) into MONOsaccharides (galactose, glucose, fructose)

I) DIGESTION

a) MOUTH/PANCREAS
-->STARCH/GLYCOGEN--(amylase)-->MALTOSE, ISOMALTOSE, MALTOTRIOSE, LIMIT DEXTRINS
-->SUCROSE and LACTOSE also enter at this step.

b) SMALL INTESTINE BRUSH BORDER

LACTOSE--(lactase)-->GALACTOSE

MALTOSE, MALTOTRIOSE, LIMIT DEXTRIN--(a-glucosidase)-->GLUCOSE

SUCROSE--(sucrase)-->FRUCTOSE

II) ABSORPTION

FRUCTOSE-->favorable conc. gradient, so transported passively by Glut-5 and Glut-2

GLUCOSE/GALACTOSE-->NOT favorable conc. gradient. "Piggy-back" w/ sodium on the sodium-glucose transporter (SGLT1)--moves Na+ back into cell after being pumped out by Na/K pump

Front 28

What are disaccharide deficiencies?

Back 28

Lactase deficiency-->lactose intolerence
SGLT-1 deficiency-->impair glucose/galactose absorption.